The present invention concerns methods for beneficially increasing HDL cholesterol levels in subjects.
Endogenous estrogen prior to menopause, and exogenous estrogen use after menopause, results in elevations of HDL cholesterol in women. This effect is often cited as a potential explanation for lower rates of heart disease in premenopausal women and postmenopausal women taking estrogen replacement. Sullivan et al., Ann Intern Med1988; 108:358-363; and Gerhard et al., Circulation1995; 92:5-8. However, there is considerable variability among women in terms of premenopausal HDL levels and changes in HDL in response to postmenopausal estrogen replacement. A significant portion of this variability has been attributed to genetic factors. Mahaney et al., Arterioscler Thromb Vasc Biol1995; 15:1730-1739; and Austin et al., Am J Hum Genet1998; 62:406-419. Allelic variants of the estrogen receptor alpha (ER-xcex1) gene that alter the expression, function, or stability of the expressed receptor protein may account for some of this variation. Functionally significant mutations in other steroid receptor genes including receptors for androgens, mineralocorticoids, vitamin D, and glucocorticoids have already been described. Being able to identify women who are likely to have a more favorable lipid response to estrogen would be useful for patients and their physicians as they weigh the risks and benefits of estrogen replacement therapy.
A first aspect of the present invention is, accordingly, a method of screening a subject for increased likelihood of having a favorable response to estrogen replacement therapy, particularly with respect to cardiovascular health (e.g., improved future cardiovascular health as compared to that found in the same patient without estrogen replacement therapy; a decreased probability of heart disease (e.g., a decreased , heart disease (i.e., high density lipoprotein (HDL) level)). The method comprises detecting the presence of at least one estrogen receptor alpha polymorphism in the subject, the presence of the estrogen receptor alpha polymorphism indicating the subject is more likely to have a favorable response to estrogen replacement therapy.
Estrogen receptor alpha polymorphisms of interest herein (that is, polymorphisms the detection of which would indicate an increased likelihood of a favorable response to estrogen replacement therapy, are, in general, the rare form of estrogen receptor alpha polymorphisms, and in particular include the rare form of polymorphisms found in the first intron of the estrogen receptor alpha gene. Examples of suitable polymorphisms include the IVS1-1415 polymorphism (also called the CIT Intron 1 polymorphism, at a position 1415 base pairs before the beginning of exon 2), the IVS1-1505 polymorphism (also called the A/G Intron 1 polymorphism, at a position 1505 base pairs before the beginning of exon 2), the IVS1-401 polymorphism (also called the PvuII polymorphism (a C/T SNP)), and the IVS1-354 polymorphism (also called the XbaI polymorphism (an A/G SNP)). The detection of the polymorphism can include detecting whether or not the subject is heterozygous or homozygous for the polymorphism, and the detection step can also include detecting two or more different such polymorphisms in the subject.
A second aspect of the present invention is a method for beneficially affecting cardiovascular health, decreasing the risk of heart disease, and/or increasing HDL levels in a subject (e.g. beneficially altering the LDLIHDL ratio), the method comprising: (a) determining the presence of at least one estrogen receptor alpha polymorphism in said subject; and then, if said estrogen receptor alpha polymorphism is present, (b) administering estrogen replacement therapy to said subject in an amount effective to beneficially affect cardiovascular health, decrease the risk of heart disease, and/or increase HDL levels in said subject. Polymorphisms of interest are as discussed above.
A further aspect of the present invention is a method of treating a subject for depressed HDL levels (i.e., depressed in absolute levels or depressed relative to LDL levels), said method comprising the steps of: selecting a subject that carries at least one estrogen receptor alpha polymorphism, and administering estrogen replacement therapy to said subject in an amount effective to increase HDL levels (e.g., beneficially alter the LDL/HDL ratio) in said subject. Polymorphisms of interest are as discussed above.
A further aspect of the present invention is the use of one or more estrogen replacement therapy active agents for the preparation of a medicament for carrying out a method as described above.
A further aspect of the present invention is the use of a means of detecting an estrogen receptor alpha polymorphism of interest in determining if a subject is suitable for treatment with hormone replacement therapy for beneficially affecting cardiovascular health, decreasing risk of heart disease, and/or raising HDL levels in that subject. Polymorphisms of interest are the same as discussed above.
Still further aspects of the present invention include kits, reagents such as oligonucleotide probes, restriction enzymes and other such means for carrying out methods as described above, the use of such reagents for the preparation of kits or diagnostic reagents for carrying out the methods described above, the use of the estrogen receptor polymorphisms described above in structuring clinical trials of estrogen replacement therapy active agents for beneficial efficacy as discussed above, and the use of the estrogen receptor polymorphisms as targets for rational drug design.
The foregoing and other objects and aspects of the present invention are explained in greater detail in the drawings herein and the specification set forth below.